Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use.

OBJECTIVE: To determine whether 1) combined oral contraceptive (COC) use affects serum levels of valproate (VPA) as well as lamotrigine (LTG) and 2) the naturally occurring high (mid-luteal) and low (early-mid follicular) reproductive steroid level phases of the menstrual cycle might affect antiepileptic drug levels as well. METHODS: This investigation compared serum antiepileptic drug levels at two timepoints during a single menstrual cycle in four groups of women with epilepsy: 12 on VPA, 12 on VPA plus COC (VPA-COC), 12 on LTG, and 12 on LTG plus COC (LTG-COC). RESULTS: Both VPA and LTG levels were lower (p < 0.01) on active COC than on inactive pill with median declines of 23.4% for the VPA-COC group and 32.6% for the LTG-COC group. Serum LTG levels showed a notable but not significant 31.3% median decline during the mid-luteal phase compared to the early-mid follicular phase in the non-COC group. The non-COC valproate group showed the least change of any group between the two measured timepoints with a decline of 8.3% (p = NS). CONCLUSIONS: The findings suggest that valproate (VPA), like lamotrigine (LTG), has substantially and significantly lower serum levels while women take active combined oral contraceptives as compared to inactive pills. Larger sample sizes will be required to determine whether LTG levels may drop significantly also during the luteal (high steroid) phase of natural menstrual cycles and whether VPA levels may show greater stability in levels across the phases of the menstrual cycle.

Stereotactic cortical resection in non-lesional extra-temporal partial epilepsy.

The presentation and treatment of a patient with extra-temporal non-lesional partial epilepsy is discussed herein. His clinical semiology was consistent with supplementary motor area seizures; however, MR imaging did not demonstrate a lesion. A region of stable cortical glucose hypermetabolism in the left frontal region was noted with 2-fluoro-2-deoxy-D-glucose (FDG)-PET. This was consistent with the frequent interictal discharges evident over the left fronto-temporal region and the stereotypic high amplitude ictal discharges arising with highest amplitude from the left frontal region. Epileptiform activity evident on an intracranial 64-point subdural recording grid placed over the left dorsolateral frontal cortex confirmed a distribution concordant with FDG-PET findings. The subsequent resection was guided by the PET and EEG findings rather than structural MR imaging, and a limited cortical resection led to an immediate and substantial reduction in seizure frequency.

Expanding the guidelines for electronic communication with patients: application to a specific tool.

In 1998, the American Medical Informatics Association (AMIA) published a white paper entitled "Guidelines for the Clinical Use of Electronic Mail with Patients," which outlined a practical framework for this interaction. Interest in the use of other Internet-based tools, such as the World Wide Web, to enhance clinical communication is increasing. In such systems, static information can be made centrally available to patients and interactive tools such as messaging systems, schedules, and individualized care regimens can be integrated within the site. Site-specific guidelines are needed to address potential problems inherent in the particular services being offered. This article presents advice on developing site-specific guidelines, with examples, based on experience gained in developing and refining guidelines for the use of PatientWeb at the Massachusetts General Hospital Department of Neurology.

The impact of a single seizure on health status and health care utilization.

PURPOSE: To assess the health status of patients after a single seizure. METHODS: We compared single-seizure patients (SS) with patients who had well-controlled epilepsy (WC), and uncomplicated hypertension (HT). Patients were adults screened from emergency and outpatient units of two urban teaching hospitals using predefined criteria. The 83 patients (SS, 30; WC, 29; HT, 24) were interviewed by phone about functional status (SF-36), comorbid illness, cause of illness, number of visits to health providers, and drug side effects. RESULTS: No significant differences were found among groups for health status, SF-36 domain, or occurrence of drug side effects. SS patients had significantly lower scores on vitality (p < 0.03) and a trend toward lower role physical function (p < 0.07) compared with age-adjusted population norms. SS reported more visits to health providers than WC or HT, and the number of visits remained high at interview 1 year later. Patient knowledge of the "reason" for the seizure was not associated with health status or number of visits. CONCLUSIONS: Health status of patients within 1 year of a single seizure is similar to that of patients with well-controlled epilepsy or hypertension, but SS patients have greater health care utilization.

Information exchange in an epilepsy forum on the World Wide Web.

The Partners Healthcare Epilepsy Service hosts an epilepsy 'Webforum'. In this paper, we describe our observations regarding who uses it, what kind of information is exchanged, how much misinformation is present and how we can better serve our patients. We examined a sample of 155 posts to the forum and 342 responses to those posts. The individual making the post and the type of questions were categorized. We also determined whether any information was objectively inaccurate. The principal users were care-givers (49%) and patients (34%). Eighty percent of the primary posts were questions. Answers were given largely by patients (38%) and care-givers (34%). The most commonly asked questions were about treatment options (31%) and the natural history of the illness (28%). In 20% of the questions, the user incidentally remarked that a health-care provider had not met their information needs. Six percent of the information was objectively inaccurate. The Web can serve as an effective means for the exchange of information between individuals with a common medical condition. We found that a small amount of misinformation is exchanged and that health-care providers are sometimes perceived as unable or unwilling to supply important health-related information.

Periodic lateralized epileptiform discharges--a critical review.

It is the purpose of this review to critically consider and organize the literature dealing with the ephemeral electroencephalographic (EEG) pattern periodic lateralized epileptiform discharges (PLEDs). Although the retrospective nature of these studies limits their ability to discuss accurately the clinical and pathophysiological aspects of this EEG entity, the available data strongly emphasize stroke as the dominant etiology and its high association with seizures. Recent evidence, particularly from functional neuroimaging studies, strongly suggests that PLEDs might reflect a key pattern for focal hyperexcitability in the penumbra zone of ischemic stroke. The authors prefer to consider PLEDs as an EEG signature of a dynamic pathophysiological state in which unstable neurobiological processes create an ictal-interictal continuum, with the nature of the underlying neuronal injury, the patient's preexisting propensity to have seizures, and the co-existence of any acute metabolic derangements all contributing to whether seizures occur or not. This review underlines the need for further sophisticated prospective controlled studies implementing early continuous EEG monitoring in order to contribute to an understanding of the incidence, dynamics, and relevance of this pattern.

Epilepsy and mental decline.

Experience with prolonged seizures in animal models and humans teaches that cellular injury and cognitive impairment can occur in epilepsy. Status epilepticus probably causes cerebral injury and cognitive dysfunction if it is of long duration; however, studies of electroconvulsive therapy do not support the idea that repeated seizures alone produce a decline in cognitive function. Although many factors related to seizures may correlate with cognitive impairment in certain groups of patients with epilepsy, prospective studies do not support the premise that cognitive impairment develops or progresses in a population of epilepsy patients. When impairment is present, its origin appears to be multifactorial. In addition to the seizures and associated seizure variables (including anticonvulsant medications), interictal epileptiform discharges and the perceptions of the patients and others also may play major roles.

Topographic mapping of somatosensory evoked potentials helps identify motor cortex more quickly in the operating room.

Median nerve somatosensory evoked potentials were recorded from exposed cerebral cortex during craniotomies. This technique is valuable when knowledge of the motor cortex location can influence surgical decisions about resection limits or biopsy sites. Two different recording techniques were compared: strips of electrodes and arrays of electrodes. The arrays recorded electrical potentials suitable for topographic mapping. We found that motor cortex could be identified more quickly when using the topographic mapping of SEPs from arrays. We conclude that topographic mapping of SEP from sensorimotor regions during craniotomies works well in general and can be done more quickly than the traditional electrode strip technique.

Fatal puerperal cerebral vasospasm and stroke in a young woman.

A woman who experienced postpartum cerebral infarction, brain edema, and death is described. Angiography implicated cerebral vasospasm as the primary etiology.

L-glutamate binding site on N18-RE-105 neuroblastoma hybrid cells is not coupled to an ion channel.

We studied the properties of the N18-RE-105 neuronal cell line to determine if its glutamate binding site represents a neurotransmitter receptor. In immunocytochemical experiments, these cells stained strongly for neurofilament, but not for glial fibrillary acidic protein. In whole-cell patch clamp experiments, cells exhibited voltage-dependent Na+, Ca2+, and K+ currents characteristic of neurons. However, perfusion with L-glutamate or other excitatory amino acids did not evoke the inward current expected of a receptor/channel complex. In binding studies, the maximum accumulation of L-[3H]glutamate by washed membrane vesicles at 37 degrees C was 69 pmol/mg protein, and half-maximal accumulation occurred at 0.64 microM. This accumulation was blocked completely by quisqualate, partially by DL-2-amino-4-phosphonobutyric acid and L-cystine, but not at all by 1 mM kainate or N-methylaspartate. L-[3H]Glutamate accumulation was stimulated by Cl-, but reduced by Na+, 0.01% digitonin, or hyperosmotic (400 mM glucose) assay medium. The release of L-[3H]glutamate from vesicles was much faster in the presence of 100 microM unlabelled glutamate than 100 microM unlabelled quisqualate or DL-2-amino-4-phosphonobutyric acid. Thus, although N18-RE-105 cells possess many neuronal properties, the results obtained are not those expected from reversible binding of L-glutamate to a receptor/channel complex, but are consistent with a Cl- -stimulated sequestration or exchange process.

GABAergic neurons in rat hippocampal culture.

The experiments described here were designed to study biochemical and histological measures of gamma-aminobutyric acid (GABA) uptake and glutamic acid decarboxylase (GAD) in primary dissociated cell cultures prepared from 17-21-day fetal rat hippocampus. Preparations from all ages of animals, except 21-day fetuses, were enriched in GABAergic neurons, when compared to the adult hippocampus in situ. These cells comprise 30-50% of the large, phase-bright, process-bearing cells in hippocampal cultures as estimated by autoradiography of GABA uptake and GAD immunocytochemistry. Neurons concentrate GABA by a relatively slow but high-affinity process (Km = 2.6 microM) that has considerably higher maximum velocity than glial uptake (Vmax = 479 pmol/mg protein/min for neurons and 31 pmol/mg protein/min for glia). No low-affinity uptake process was noted in neurons or glia. GABA uptake into neurons was competitively inhibited by cis-4-OH-nipecotic acid (Ki = 39 +/- 11 microM). These cultures also possess considerable GAD activity, up to 6 nmol/mg protein/min in one-month-old cultures, which approximates that of the adult hippocampus. Both GABA uptake and GAD activity increased with time in culture. The enrichment of GABAergic markers indicates that this preparation may be useful for the detailed study of hippocampal GABAergic neurons.

Factors affecting the phosphorylation of a 41,000 dalton protein of hippocampal subcellular fractions.

The phosphorylation of the alpha-subunit of mitochondrial pyruvate dehydrogenase may be involved in the development of long-term potentiation in the hippocampus. Study of this hypothesis is hampered by variability in the incorporation of 32P into pyruvate dehydrogenase of hippocampal subcellular preparations, in vitro. 32P from [gamma-32P]ATP was incorporated into pyruvate dehydrogenase present in mitochondria and in a membrane-enriched synaptic particulate fraction from hippocampus. However, the presence of the synaptic fraction decreased isotopic labeling of the mitochondrial protein. This effect was not due to inhibition of the protein kinase or activation of a protein phosphatase, but the rate of ATP hydrolysis was found to be higher in the synaptic fraction than in the mitochondria (34 nmol/mg protein/min vs 14 nmol/mg protein/min). These data raise a variety of questions about the interpretation of the in vitro phosphorylation assay. It is concluded that variability in in vitro labeling can be minimized if the effect of ATP hydrolysis is diminished by use of a higher concentration of ATP. In addition, these data indicate that quantitative comparisons of the in vitro phosphorylation of diverse subcellular preparations must take into account differential rates of ATP hydrolysis.

Long-term potentiation in the hippocampal slice: possible involvement of pyruvate dehydrogenase.

Tetanic stimulation of fibers in the hippocampal slice preparation produces long-term potentiation (LTP) and also decreases the in vitro incorporation of phosphate into the alpha subunit of pyruvate dehydrogenase (alpha PDH). This paper describes 6 experiments that were undertaken to replicate this observation. Hippocampal slices were incubated in a specially designed chamber and stimulated with a tungsten wire electrode in the stratum radiatum for 1 s at 100 Hz. Two minutes after the tetanus, the stimulated slices were removed alternately with control (not tetanized) slices and each group was pooled for subcellular fractionation and labeling of the fractions with [32P]ATP. Proteins were separated by electrophoresis and relative 32P contents of 41K and 50K protein bands were studied. Tetanic stimulation of the stratum radiatum did not affect subsequent phosphorylation of a 50K Mr protein that has been reported to be altered by perforant path activation. Stimulation also had no effect on pyruvate dehydrogenase enzyme activity or on the ratio of active (dephosphorylated) to inactive enzyme. In most cases tetanic stimulation produced no significant change in the in vitro phosphorylation of this enzyme. Only under one set of conditions, labeling with 250 microM [gamma-32P]ATP for 10 s, was a decrease in the in vitro labeling of alpha PDH shown to be statistically significant. These findings suggest that LTP is not necessarily accompanied by an initial change in PDH phosphorylation level or activity but may be associated with a decrease in the kinase activity directed toward this protein.

Effects of calcium, strontium, and barium ions on phosphorylation of hippocampal proteins in vitro.

Calcium ion alone or in the presence of added calmodulin stimulated in vitro transfer of 32P from [gamma 32P]ATP into several proteins of mitochondrial and synaptosomal particulate fractions from rat brain. Strontium ion was capable of substituting for calcium ion in this stimulation, but barium ion lacked this capacity. These results bring into question the hypothesis that calcium-dependent protein phosphorylation of synaptic proteins is intrinsic to neurotransmitter release during neurotransmission, but they do not rule out that possibility.

14C-dopamine microinjected into the brain-stem of the rat: dispersion kinetics, site content and functional dose.

A morphological analysis was undertaken of both the dispersion characteristics and tissue content of dopamine (DA) microinjected acutely into the brain-stem of the anesthetized rat. 14C-DA, with a specific activity of 56-62 mCi/mMol, was infused unilaterally into the pars compacta of the substantia nigra in one of four test volumes: 0.5, 1.0, 4.0 or 8.0 microliters. The concentration of the 14C-DA solution was 1.0 microCi/microliter, equivalent to 3.01 micrograms/microliters, which was delivered at an injection rate of 1.0 microliter per 45 sec. At an interval of either one min or 15 min following the microinjection, the rat's brain was removed rapidly from its calvarium, flash frozen and then cut in the coronal plane on a freezing microtome in 500 micron slabs. After each of the respective serial slabs was mounted on glass, the Eik Nes-Brizzee trochar technique for the discrete removal of tissue samples was used to obtain 0.5 mm dia. cylindrical plugs of meso-diencephalic tissue at distances from the site of injection ranging from 0.5 to 2.5 mm, center to center. Each sample plug was subsequently solubilized and 14C-DA activity quantitated by liquid scintillation spectrometry. The results show that regardless of volume, the spatial patterning of the microinjected solution assumes a tear-drop or pear shape, not a sphere. Further, as the volume of the injection is increased from 0.5 to 8.0 microliters, the magnitude of the dispersion of 14C-DA is enhanced throughout the surrounding parenchyma, but not in a linear fashion.(ABSTRACT TRUNCATED AT 250 WORDS)